Condensation reaction between α-amino acid phenylhydrazides and carbonyl compounds

Article abstract of DOI:10.1002/ejoc.200300251

The natural α-amino acid phenylhydrazides 1a-d readily react with the aldehydes 2a-d and ketones 2e-h to produce the 3-(phenylamino)imidazolidin-4-one derivatives 4 in good yields. Their structures were confirmed by X-ray structural analysis. Polycyclic s

Full text of DOI:10.1002/ejoc.200300251

FULL PAPER
Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl
Compounds
Giancarlo Verardo,*[a] Paola Geatti,[a] Paolo Martinuzzi,[a] Marcello Merli,[b] and
Nicoletta Toniutti[a]
Keywords: Amino acids / α-Amino acid phenylhydrazides / Cyclisation reactions / Heterocycles
The natural α-amino acid phenylhydrazides 1a−d readily re-
act with the aldehydes 2a−d and ketones 2e−h to produce
phenyl-2-(phenylamino)-2,9,10a-triazacyclopenta[b]fluoren-
3-one (5dc) and 4,6-diphenyl-7-(phenylamino)-3,4,6,7,8a,9-
the 3-(phenylamino)imidazolidin-4-one derivatives 4 in good hexahydro-8H-diimidazo[1,5-a:4Ј,5Ј-d]pyridin-8-one (5ec),
yields. Their structures were confirmed by X-ray structural
analysis. Polycyclic systems were obtained from the reaction
respectively.
of L-tryptophan phenylhydrazide (1d) and L-histidine phenyl- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
hydrazide (1e) with benzaldehyde (2c), which gave 1,10-di-
Germany, 2003)
Introduction
zolidin-4-ones that we have prepared in our laboratory do
not appear to have precedent in the chemical literature.
We have recently described the products — derivatives
of the six-membered heterocyclic hexahydro-1,2,4-triazin-6-
one system —from the reaction of some phenylhydrazides
of natural amino acids with aqueous formaldehyde.[1] In an
attempt to extend this reaction scheme to more complex
carbonyl compounds, we have established unambiguously,
by X-ray analysis, that the structure of the condensation
derivatives obtained are five-membered heterocycles, na-
mely imidazolidin-4-ones, and not six-membered rings. This
finding prompted us to study this reaction to investigate
how the nature of both the carbonyl compound and the
side chain of the α-amino acid phenylhydrazide employed
influence the structures of these condensation products.
The imidazolidin-4-one ring has been widely studied be-
cause of its pharmacological activity, which is influenced
by the type and position of the substituents present in the
heterocycle. Among all the reported procedures, the most
efficient are those involving the condensation reaction be-
tween carbonyl compounds and α-amino,[2] α-(alkylami-
no),[2a,3] α-(methylsulfonylamino),[2c,4] and α-(benzyloxycar-
bonylamino)[2c,4,5] acid amides. The same reaction scheme
has been followed to obtain 3-hydroxy-4-imidazolidinone[6]
starting from the hydroxamic derivatives of glycine and ala-
nine. Surprisingly, the 3-(phenylamino)-substituted imida-
Results and Discussion
When an α-amino acid phenylhydrazide of type 1 and a
carbonyl compound like 2 were mixed under appropriate
experimental conditions, a ring-forming condensation took
place yielding imidazolidin-4-ones (4, Scheme 1).
Initially, we examined the behaviour of a variety of car-
bonyl compounds with the phenylhydrazides of alanine
(1a), phenylalanine (1b) and leucine (1c), amino acids
whose side chains do not induce further reactions other
than the cyclisation to 4. As expected, the reactivity de-
pended both on the electrophilicity and the bulkiness of the
substituents of the carbonyl compound.
The reaction of propanal (2a), benzaldehyde (2c) and 2-
nitrobenzaldehyde (2d) in hot EtOH (50Ϫ70 °C) occurred
within 2 h using a slight excess of 2. We did not observe
any significant difference in reactivity among these alde-
hydes, but ring closure did not occur when the sterically
hindered 2,2-dimethylpropanal (2b) was used in connection
with 1a, even under the forcing reaction conditions pre-
viously described. The use of an acidic catalyst (PTSA) and
toluene as solvent (6 h, 60 °C) allowed us to obtain a practi-
cally quantitative yield of the cyclisation product 4ab. In
fact, under these experimental conditions, both 2b and the
imine 3ab formed were more reactive because of partial pro-
tonation. The reaction temperature was kept at 60 °C be-
cause of the low stability of 2b.
[a]
`
Dipartimento di Scienze e Tecnologie Chimiche, Universita di
Udine,
Via del Cotonificio 108, 33100 Udine, Italy
Fax: (internat.) ϩ 39-0432/558803
E-mail: giancarlo.verardo@dstc.uniud.it
Centro di Studi per la Cristallochimica e la Cristallografia del
[b]
When we extended this process to ketones under the same
experimental conditions used for the sterically unhindered
`
CNR, Universita di Pavia,
Via Abbiategrasso 209, 27100 Pavia, Italy
3840
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300251
Eur. J. Org. Chem. 2003, 3840Ϫ3849

Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl Compounds
FULL PAPER
Scheme 1. Reagents and conditions: a) 2 (1.10 equiv.), EtOH, 70 °C, 2 h; b) 2 (1.10 equiv.), EtOH, 50 °C, 2 h; c) 2 (1.05 equiv.), EtOH,
50 °C, 3 h; d) 2 (3.00 equiv.), PTSA (0.10 equiv.), toluene, 60 °C, 6 h; e) 2 (5.00 equiv.), EtOH, 50 °C, 5 h; f) 2 (2.00 equiv.), PTSA (0.10
equiv.), toluene, 85 °C, 24 h
aldehydes 2a and 2cϪd, the rates of the reactions decreased (2g) appeared not to react at all without the use of acid
because of the lower electrophilicity of their carbonyl catalysis. To avoid problems in the purification of the final
groups. With acetone (2e), 2-pentanone (2f) and 4-nitroace- products, the reactions involving 2fϪh were carried out in
tophenone (2h), an excess (fivefold) of the ketone and the presence of PTSA, using toluene as solvent and with
longer reaction times (5Ϫ16 h) were required to obtain the twice the stoichiometric amount of ketone.
corresponding imidazolidin-4-ones (4). In contrast to the
From this comparison of the reactivity of these four ke-
more electrophilic 4-nitroacetophenone (2h), acetophenone tones, we infer that the electrophilicity of the carbonyl car-
Table 1. Yields and some properties of compounds 4
4
Yield (%)[a]
A/B ratio[b]
M.p. (°C)
[α]D (c, MeOH)
Ϫ61.7 (1.0)
Formula (mass)
C, H, N found (C, H, N calcd.)
ab
ac
ae
ag
ba
bc
bd
be
bf
bh
cc
cd
ce
dc
de
ee
86
70
98
82
83
75
90
95
89
80
72
91
98
84
98
95
100:0
52:48
125
197 (dec.)
106
glass
108
62
C14H21N3O (247.34)
C16H17N3O (267.33)
C12H17N3O (219.29)
C17H19N3O (281.36)
C18H21N3O (295.38)
C22H21N3O (343.43)
C22H20N4O3 (388.43)
C18H21N3O (295.38)
C20H25N3O (323.44)
C23H22N4O3 (402.45)
C19H23N3O (309.41)
C19H22N4O3 (354.41)
C15H23N3O (261.37)
C24H22N4O (382.46)
C20H22N4O (334.42)
C15H19N5O (285.35)
67.96, 8.53, 17.00 (67.98, 8.56, 16.99)
71.86, 6.39, 15.74 (71.89, 6.41, 15.72)
65.70, 7.80, 19.18 (65.73, 7.81, 19.16)
72.59, 6.80, 14.90 (72.57, 6.81, 14.93)
73.21, 7.15, 14.20 (73.19, 7.17, 14.23)
76.92, 6.18, 12.25 (76.94, 6.16, 12.24)
68.00, 5.21, 14.40 (68.03, 5.19, 14.42)
73.21, 7.15, 14.22 (73.19, 7.17, 14.23)
74.24, 7.78, 13.01 (74.27, 7.79, 12.99)
68.62, 5.54, 13.90 (68.64, 5.51, 13.92)
73.77, 7.51, 13.56 (73.76, 7.49, 13.58)
64.41, 6.24, 15.83 (64.39, 6.26, 15.81)
68.92, 8.86, 16.10 (68.93, 8.87, 16.08)
75.35, 5.81, 14.63 (75.37, 5.80, 14.65)
71.80, 6.64, 16.77 (71.83, 6.63, 16.75)
63.11, 6.72, 24.55 (63.14, 6.71, 24.54)
ϩ100.0 (1.0)
74:26
55:45
57:43
50:50
80
(glass)
(glass)
86
45
135
(glass)
144
124
Ϫ19.8 (0.8)
ϩ57.2 (2.0)
60:40
77:33
60:40
50:50
50:50
Ϫ19.6 (0.8)
ϩ33.8 (0.7)
164
[a]
[b]
1
Isolated yields. Diastereoisomer ratio (A/B) determined by H NMR spectroscopy.
Eur. J. Org. Chem. 2003, 3840Ϫ3849
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3841

G. Verardo, P. Geatti, P. Matinuzzi, M. Merli, N. Toniutti
FULL PAPER
bon atom is the key factor in both the initial and sub-
sequent steps of the reactions sequence.
Figure 1 shows that even if the amino nitrogen atom of
the phenylhydrazide moiety of 1 is more reactive[7] than the
The configuration of the stereocentre of the amino acid amide one, the condensation reaction involves the latter ex-
was retained in the corresponding phenylhydrazide, but, clusively to give a five-membered ring. The six-membered
with the exception of 2-tert-butyl-5-methyl-3-(phenylamino)- ring structure proposed for the condensation products ob-
imidazolidin-4-one (4ab), which contains the bulky tert-bu- tained from formaldehyde[1] might be incorrect, but, unfor-
1
tyl group, the H NMR spectroscopic analysis of the reac- tunately, we have not been able to obtain suitable crystals
tion mixtures reveals the presence of two diastereoisomers for X-ray structural analysis.
in ca. 1:1 ratio (Table 1) in all cases where the substituents
We have also investigated the reaction of phenylhydra-
R1 and R2 of the carbonyl group are different. This absence zides of amino acids that bear reactive sites in their side
of asymmetric induction by the chiral centre of 1 can be chains, such as tryptophan (1d) and histidine (1e), with ben-
taken as an indication that the final step is very fast, i.e., zaldehyde (2c) and acetone (2e). While the reaction of both
the intermediate is a very reactive species.
of these phenylhydrazides with 2e gave the expected imida-
We infer the formation of a cyclic adduct from the pres- zolidin-4-ones 4de and 4ee under the experimental con-
ence of one or, when two diastereoisomers are produced, ditions previously described (EtOH, 50 °C), with 2c their
two signals in the range δ ϭ 70Ϫ80 ppm in the 13C NMR behaviour was different. In fact, after 3 h in EtOH at 50 °C
spectra (Table 2) belonging to the NϪCϪN moiety of the with a slight excess of 2c, tryptophan phenylhydrazide (1d)
1
ring. H NMR spectra of compounds 4 (Table 2), derived gave only a mixture of the two diastereoisomers of 5-(1H-
from the condensation reaction of 1 with benzaldehyde (2c), indol-3-ylmethyl)-2-phenyl-3-(phenylamino)imidazolidin-4-
show two doublets, one for each diastereoisomer, in the one (4dc), but, when the reaction was carried out for 40 h
range δ ϭ 5.3Ϫ5.7 ppm for the proton of the closed ring with 3 equiv. of 2c, a compound formed by double ring
with a coupling constant of 1.0Ϫ1.5 Hz with the proton of closure was obtained, namely 1,10-diphenyl-2-(phenylam-
the α-chiral centre. These signals are shifted downfield (δ ϭ ino)-1,2,3a,4,9,10a-triazacyclopenta[b]fluoren-3-one (5dc,
6.2Ϫ6.4 ppm; J ϭ 1.0Ϫ1.3 Hz) in the 2-nitrobenzaldehyde Scheme 2). The reaction of histidine phenylhydrazide (1e)
derivatives 4bd and 4cd, and upfield (δ ϭ 4.2Ϫ4.4 ppm), with 2c was not be limited to the production of 5-(1H-imid-
as two multiplets, in the propanal derivative 4ba. Further azol-4-ylmethyl)-2-phenyl-3-(phenylamino)imidazolidin-4-
confirmation for the ring closure is the lack, in the 1H one (4ec) because a second, and at least equally fast, ring
NMR spectra of 4, of one of the two proton resonances of closure involving the imidazole ring gave a tricyclic com-
the NHNHPh skeleton of
1
in the range
δ
ϭ
pound, namely 4,6-diphenyl-7-(phenylamino)-3,4,6,7,8a,9-
hexahydro-8H-diimidazo[1,5-a:4Ј,5Ј-d]pyridin-8-one (5ec,
6.0Ϫ10.0 ppm.[1]
The presence of the imidazolidinone ring in compounds Scheme 2).
4 was confirmed unambiguously by X-ray diffraction analy-
The 13C NMR spectra of 5dc and 5ec obtained using the
sis of 5-isobutyl-2-(2-nitrophenyl)-3-(phenylamino)imidazo- PENDANT method show signals of a number of tertiary
lidin-4-one (4cd). The resulting structure, shown in Fig- and quaternary carbon atoms in the aromatic region that
ure 1, has the following features (see Figure 1 for atom are consistent with a second ring closure involving the 2-
numbering):
position of the indole unit in 4dc and the 5-position of the
Ϫ There are two diastereoisomers present, both of which imidazole unit in 4ec. On the basis of the experimental data,
retain the same configuration of the α-chiral centre at C5 the formation of the imidazolidin-4-one ring was the first
of the starting phenylhydrazide 1a.
step of the reaction sequence leading to 5 in reactions of
Ϫ The two diastereoisomers have opposite configurations both 1d and 1e, with the subsequent electrophilic substi-
at the ring closure carbon atom (C6) but, apart from that, tution being faster for the imidazole ring than for the indole
the geometrical parameters of the two molecules are similar. ring. These results are in contrast with those obtained from
Ϫ The imidazolidinone ring is almost planar — it is dis- the reaction involving tryptophan phenylhydrazide hydro-
torted slightly by the steric requirements of the substituents. chloride and formaldehyde[1] because we observed only the
The N2ϪC7ϪC5 bond angle has the peculiarity of being product of ring closure at the 2-position of the indole ring,
much smaller (106.3° in diastereoisomer A and 109.2° in i.e., 1,2,3,4-tetrahydro-3-(2-phenylcarbazoyl)-β-carboline.
1
diastereoisomer B) than that expected for an sp2-hybridized
carbon atom.
Surprisingly, the H and 13C NMR spectra of 5dc and
5ec reveal a single set of peaks consistent with the presence
Ϫ The nitrophenyl and aminophenyl groups are oriented of a single diastereoisomer. The structure of 5dc (Figure 2)
anti to one another and are almost perpendicular to the was determined tentatively by means of NMR spectroscopy.
imidazolidinone ring (torsion angles N1ϪC6ϪC8ϪC9 and
Two-dimensional C,H correlation experiments allowed us
C7ϪN2ϪN4ϪC14 are 93.6 and 73.2°, respectively, in dia- to assign the doublet centred at δ ϭ 5.00 ppm (J ϭ 2.4 Hz)
1
stereoisomer A and Ϫ89.7 and Ϫ61.8°, respectively, in dia- in the H NMR spectrum obtained in [D6]acetone to the
stereoisomer B).
benzylidene proton (H4) derived from the benzaldehyde
Ϫ The two nitrogen atoms of the phenylhydrazide moiety unit involved in the imidazolidinone ring closure and the
and the phenyl ring are approximately coplanar (the torsion doublet at δ ϭ 5.14 ppm (J ϭ 0.5 Hz) to that of the second
angle C19ϪC14ϪN4ϪN2 is 12.4° in diastereoisomer A and ring closure (H5) involving the 2-position of the indole sys-
Ϫ17.7° in diastereoisomer B).
tem. H,H-Decoupling and H,H-COSY spectra of 5dc
3842
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3840Ϫ3849

Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl Compounds
Table 2. Spectroscopic and mass spectrometric data for compounds 4
FULL PAPER
IR (KBr), ν˜ (cmϪ1
)
1H NMR[a], δ (ppm), J (Hz)
13C NMR, δ (ppm)
MS (70 eV), m/z (%)
4ab 3300, 3220, 3040, 3000,
2960, 2870, 1710, 1605,
1500, 1485, 1440, 1400,
1390, 1380, 1310, 1230,
1195, 1180, 1140, 870,
775, 745, 690
4ac 3280, 1718, 1605, 1500,
1455, 1395, 1315, 1270,
1180, 1080, 1030, 850,
755, 700
0.99 (s, 9 H, 3 ϫ CH3), 1.37 (d, J ϭ 6.6 Hz,
3 H, *CHCH3), 1.88 (br. s, 1 H, NH), 3.67 (q,
J ϭ 6.6 Hz, 1 H, *CH), 4.48 (s, 1 H, NCHN),
6.46 (s, 1 H, PhNH), 6.58Ϫ6.72 (m, 2 H,
18.5, 25.7, 35.1, 52.9, 80.1, 114.0, 247 [Mϩ] (31), 190 (100),
121.2, 129.6, 146.1, 176.0[b]
134 (8), 119 (45), 112 (17),
107 (8), 98 (27), 93 (13),
92 (40), 86 (30), 77 (14),
69 (11), 65 (18), 44 (18)
Harom.), 6.80Ϫ6.92 (m, 1 H, Harom.),
[b]
7.10Ϫ7.24 (m, 2 H, Harom..
)
1.50 (d, J ϭ 6.86 Hz, 3 H ϩ 3 H, *CHCH3
A ϩ B), 2.55 (br. s, 1 H ϩ 1 H, NH A ϩ B), 3.82
(dq, J1 ϭ 6.9, J2 ϭ 1.2, 1 H, *CHCH3 A), 3.92
(dq, J1 ϭ 6.9, J2 ϭ 1.1 Hz, 1 H, *CHCH3 B),
5.56 (d, J ϭ 1.2 Hz, 1 H, NCHN A), 5.61 (d,
18.0, 18.5, 52.5, 53.3, 74.4,
74.8, 113.6, 113.9, 121.4,
121.5, 126.7, 127.4, 128.9,
129.0, 129.1, 129.2, 129.3,
129.7, 137.6, 138.4, 145.0,
267 [Mϩ] (88), 134 (15),
133 (29), 132 (100), 106
(53), 105 (28), 92 (10), 91
(9), 77 (25), 65 (13)
J ϭ 1.1 Hz, 1 H, NCHN B), 5.67 (s, 1 H, PhNH A), 145.3, 174.5, 174.7[b]
5.74 (s, 1 H, PhNH B), 6.56Ϫ6.74 (m,
2 H ϩ 2 H, Harom. A ϩ B),
6.80Ϫ6.96 (m, 1 H ϩ 1 H,
Harom. A ϩ B), 7.08Ϫ7.44 (m, 7 H ϩ 7 H,
Harom. A ϩ B)[b]
1.30Ϫ1.50 [m, 9 H, *CHCH3 ϩ C(CH3)2], 2.02
(br. s, 1 H, NH), 3.58 (q, J ϭ 6.9 Hz, 1 H,
4ae 3300, 1685, 1595, 1490,
1390, 1370, 1310, 1260,
1235, 1210, 1175, 1155,
17.8, 24.9, 27.6, 52.6, 77.3,
114.0, 121.5, 129.5, 147.5,
176.6[b]
219 [Mϩ] (91), 134 (19),
112 (15), 105 (13), 93 (29),
92 (27), 85 (43), 84 (100),
77 (28), 65 (17), 58 (56)
281 [Mϩ] (80), 147 (16),
146 (100), 134 (10), 121
(8), 120 (82), 119 (17), 105
(39), 104 (36), 103 (22), 93
(12), 92 (13), 78 (15),
77 (54)
*CH), 6.22 (s, 1 H, PhNH), 6.73Ϫ6.94 (m,
[b]
1100, 1000, 835, 740, 690 3 H, Harom.), 7.13Ϫ7.26 (m, 2 H, Harom.
)
4ag 3280, 1710, 1605, 1500,
1450, 1390, 1310, 1245,
1110, 755, 700, 670, 630
1.41 (d, J ϭ 6.8 Hz, 3 H, *CHCH3 A), 1.46
17.9, 18.4, 25.5, 27.6, 52.4,
52.9, 79.5, 79.6, 114.0,
114.1, 114.4, 121.5, 121.7,
126.0, 126.5, 128.6, 128.9,
129.1, 129.3, 129.5, 142.3,
142.8, 146.6, 147.2, 175.2,
176.1[b]
(d, J ϭ 6.8 Hz, 3 H, *CHCH3 B), 1.79 (s, 3 H,
CCH3 A), 1.82 (s, 3 H, CCH3 B), 1.95 (br. s,
1 H ϩ 1 H, NH A ϩ B), 3.52 (q, J ϭ 6.8 Hz,
1 H, *CH B), 3.54 (q, J ϭ 6.8 Hz, 1 H, *CH A),
5.94 (s, 1 H, PhNH A), 6.11 (s, 1 H, PhNH B),
6.58Ϫ7.62 (m, 10 H ϩ 10 H,
Harom. A ϩ B)[b]
4ba 3270, 1700, 1600, 1500,
0.78 (t, J ϭ 7.5 Hz, 3 H, CH3 A), 0.89 (t,
J ϭ 7.5 Hz, 3 H, CH3 B), 1.05Ϫ1.31 (m,
8.1, 8.2, 26.3, 26.4, 36.4,
36.7, 57.6, 58.5, 74.0, 75.1,
113.3, 113.6, 121.0, 121.1,
126.9, 127.0, 128.6, 128.7,
128.9, 129.0,129.8, 130.0,
136.1 136.2, 145.8, 146.4,
173.5,175.2[b]
295 [Mϩ] (100), 266 (15),
204 (29), 160 (70), 147
(15), 134 (25), 133 (5), 131
(31), 120 (13), 93 (14), 92
(20), 91 (19), 65 (11), 58
(15)
1450, 1440, 1260, 1240,
1200, 1180, 1025, 920, 890, 1 H, CH3CHH A), 1.37Ϫ1.62
810, 755, 700, 665
(m, 1 H, CH3CHH B),
1.64Ϫ1.88 (m, 1 H ϩ 1 H, CH3CHH A ϩ B),
2.15 (br. s, 1 H ϩ 1 H, NH A ϩ B), 2.98Ϫ3.28
(m, 2 H ϩ 2 H, *CHCH2 A ϩ B),
3.76Ϫ3.85 (m, 1 H, *CH A), 3.85Ϫ3.94
(m, 1 H, *CH B), 4.27 (ddd, J1 ϭ 7.4,
J2 ϭ 2.9, J3 ϭ 1.1 Hz,
1 H, NCHN B), 4.36 (ddd, J1 ϭ 7.9, J2 ϭ 3.0,
J3 ϭ 1.0 Hz, 1 H, NCHN A),
6.18 (s, 1 H, PhNH A),
6.25 (s, 1 H, PhNH B), 6.38Ϫ6.48 (m, 2 H,
Harom. B),
6.52Ϫ6.62 (m, 2 H, Harom. A), 6.80Ϫ6.92
(m, 1 H ϩ 1 H, Harom. A ϩ B), 7.04Ϫ7.20 (m,
2 H ϩ 2 H, Harom.. A ϩ B), 7.22Ϫ7.42
(m, 5 H ϩ 5 H, Harom. A ϩ B)[b]
2.24 (br. s, 1 H ϩ 1 H, NH A ϩ B), 3.08Ϫ3.25
(m, 2 H ϩ 1 H, *CHCH2 A ϩ *CHCHH B),
3.34 (dd, J1 ϭ 14.0, J2 ϭ 5.6 Hz, 1 H,
4bc 3290, 1710, 1600, 1500,
1450, 1395, 1335, 1260,
1225, 1175, 1155, 1110,
37.4, 38.4, 58.5, 59.0, 75.0,
75.7, 114.3, 114.7, 122.0,
122.1, 127.4, 127.7, 127.8,
128.2, 129.4, 129.5, 129.6,
129.7, 129.8, 129.9, 130.0,
130.3, 130.7, 130.8, 137.0,
137.1, 138.0, 139.4, 145.6,
145.7, 173.3, 174.0[b]
343 [Mϩ] (100), 209 (12),
208 (21), 146 (11), 134
(10), 131 (16), 118 (11),
117 (18), 106 (29), 104
(19), 92 (13), 91 (22)
1080, 1025, 750, 700, 665, *CHCHH B), 4.00Ϫ4.10 (m, 1 H, *CH A),
620
4.14Ϫ4.24 (m, 1 H, *CH B), 5.34 (d, J ϭ
1.5 Hz, 1 H, NCHN B), 5.43 (d, J ϭ 1.3 Hz, 1
H, NCHN A), 5.46 (s, 1 H, PhNH A), 5.54 (s,
1 H, PhNH B), 6.30Ϫ6.38 (m, 2 H, Harom.. A),
6.51Ϫ6.60 (m, 2 H, Harom.. B), 6.81Ϫ6.92 (m, 2
H ϩ 2 H, Harom.. A ϩ B), 7.04Ϫ7.46 (m, 11 H ϩ
11 H, Harom.. A ϩ B)[b]
4bd 3280, 1710, 1600, 1530,
1500, 1390, 1350, 1305,
1260, 1180, 1110, 1080,
1030, 855, 785, 750, 700,
675, 620
2.67 (br. s, 1 H ϩ 1 H, NH A ϩ B), 2.98Ϫ3.32
(m, 2 H ϩ 2 H, *CHCH2 A ϩ B), 3.91Ϫ4.02
(m, 1 H, *CH A), 4.06Ϫ4.17 (m, 1 H, *CH
B), 5.95 (s, 1 H, PhNH A), 6.10 (s, 1 H,
PhNH B), 6.17 (d, J ϭ 1.2 Hz, 1 H, NCHN
B), 6.23 (d, J ϭ 1.3 Hz, 1 H, NCHN A), 6.35Ϫ
6.45 (m, 2 H, Harom.. B), 6.47Ϫ6.57 (m, 2 H,
37.4, 39.0, 57.6, 58.9, 70.4,
70.8, 114.1, 114.3, 122.0,
122.2, 124.8, 125.7, 127.2,
127.7, 127.8, 128.9, 129.4,
129.6, 129.9, 130.4, 130.5,
133.6, 134.0, 134.1, 134.4,
136.2, 136.3, 137.7, 145.3,
145.5, 149.8, 150.5, 172.9,
173.6[b]
388 [Mϩ] (100), 254 (24),
151 (42), 134 (58), 131
(28), 120 (61), 118 (19),
108 (39), 107 (19), 105
(25), 104 (18), 93 (24), 92
(47), 91 (84), 77 (28)
Harom.. A), 6.73Ϫ6.93 (m, 1 H ϩ 1 H, Harom..
A
ϩ B), 7.01Ϫ7.64 (m, 10 H ϩ10 H, Harom.. A ϩ
B), 7.70Ϫ7.80 (m, 1 H, Harom.. A), 7.85Ϫ7.95
(m, 1 H, Harom.. B)[b]
Eur. J. Org. Chem. 2003, 3840Ϫ3849
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3843

G. Verardo, P. Geatti, P. Matinuzzi, M. Merli, N. Toniutti
FULL PAPER
Table 2. (Continued)
IR (KBr), ν˜ (cmϪ1
)
1H NMR[a], δ (ppm), J (Hz)
13C NMR, δ (ppm)
MS (70 eV), m/z (%)
4be
4bf
3280, 3040, 2990, 1710,
1605, 1500, 1455, 1445,
1440, 1395, 1360, 1260,
1240, 1180, 1155, 755, 700,
610
1.17 (s, 3 H), 1.32 (s, 3 H), 1.92 (br. s, 1 H,
NH), 3.05 and 3.32 (AB of ABX, 2 H, JAB
14.1, JAX ϭ JBX ϭ 4.8 Hz, *CHCH2), 3.84
(app t, 1 H, *CH), 5.96 (s, 1 H, PhNH), 6.45Ϫ
6.58 (m, 2 H, Harom..), 6.82Ϫ6.95 (m, 1 H,
25.5, 27.2, 36.5, 57.8, 77.5, 295 [Mϩ] (100), 160 (45),
ϭ
114.4, 121.9, 127.9, 129.5,
129.6, 130.7, 136.5, 147.6,
175.4[c]
134 (13), 131 (21), 104
(28), 98 (14), 92 (28), 91
(26), 77 (15), 65 (16), 58
(40)
Harom..), 7.07Ϫ7.20 (m, 2 H, Harom..), 7.21Ϫ7.42
[c]
(m, 5 H, Harom.
)
3259, 3063, 3006, 2962,
2932, 2872, 1704, 1603,
1496, 1455, 1396, 1306,
1250, 1218, 1176, 1157,
1141, 1088, 749, 695, 668,
603, 505
0.74 (t, J ϭ 7.0 Hz, CH2CH3 A), 0.92 (t, J ϭ
7.1 Hz, CH2CH3 B), 1.07 (s, 3 H, CH3 B),
1.30 (s, 3 H, CH3 A), 1.06Ϫ1.65 (m, 4 H ϩ 4
H, CH2CH2 A ϩ B), 1.91 (br. s, 1 H ϩ 1 H,
NH A ϩ B), 2.93Ϫ3.12 (m, 1 H ϩ 1 H,
*CHCHH A ϩ B), 3.16Ϫ3.40 (m, 1 H ϩ 1 H,
*CHCHH A ϩ B), 3.77Ϫ3.89 (m, 1 H ϩ 1 H,
*CH A ϩ B), 5.99 (s, 1 H, PhNH A), 6.05 (s,
1 H, PhNH B), 6.40Ϫ6.50 (m, 2 H, Harom.. B),
6.52Ϫ6.62 (m, 2 H, Harom.. A), 6.79Ϫ6.93 (m, 1
H ϩ 1 H, Harom.. A ϩ B), 7.03Ϫ7.44 (m, 7 H
ϩ 7 H, Harom.. A ϩ B)[b]
1.49 (s, 3 H, CH3 A), 1.79 (s, 3 H, CH3 B),
2.29 (br. s, 1 H ϩ 1 H, NH A ϩ B), 3.04Ϫ3.47
(m, 2 H ϩ 2 H CH2 A ϩ B), 3.69Ϫ3.87 (m, 1
H, *CH A), 4.04Ϫ4.18 (m, 1 H, *CH B), 6.12
(s, 1 H, PhNH B), 6.20 (s, 1 H, PhNH A),
6.35Ϫ6.60 (m, 2 H ϩ 2 H, Harom.. A ϩ B),
6.72Ϫ7.61 (m, 8 H ϩ 10 H, Harom.. A ϩ B),
14.6, 14.7, 16.9, 17.7, 23.6, 323 [Mϩ] (100), 232 (14),
25.8, 36.6, 36.7, 41.5, 41.7, 188 (56), 134 (10), 131
57.5, 58.2, 79.4, 79.5,
114.2, 114.4, 121.4, 121.6,
127.6, 127.7, 129.1, 129.2,
129.3, 129.4, 130.5, 130.7,
136.2, 136.6, 147.2, 147.3,
175.0, 175.2[b]
(23), 126 (15), 105 (18),
104 (19), 98 (13), 93 (17),
92 (33), 91 (33), 86 (50),
77 (15), 65 (16), 42 (16)
4bh
3428, 1713, 1602, 1519,
1496, 1455, 1380, 1337,
1261, 1096, 1026, 859, 803,
756
25.1, 26.5, 35.4, 37.4, 55.8, 402 [Mϩ] (100), 267 (35),
57.0, 77.8, 78.2, 113.5,
165 (42), 164 (25), 149
(34), 134 (61), 131 (83),
119 (52), 108 (27), 103
(55), 93 (55), 92 (43), 91
(70), 77 (41), 65 (31)
113.8, 121.4, 121.5, 123.1,
123.5, 126.7, 126.8, 127.4,
127.6, 128.7, 128.8, 128.9,
129.9, 130.2, 134.9, 135.1,
145.7, 146.2, 147.5, 147.7,
7.78Ϫ7.90 (m, 2 H, Harom.. A), 7.95Ϫ8.06 (m, 2 H, 148.9, 149.0, 172.7,
Harom.. B), 8.13Ϫ8.23 (m, 2 H, Harom.. A)[b]
0.93Ϫ1.07 [m, 6 H ϩ 6 H, CH(CH3)2 A ϩ B],
1.44Ϫ1.72 [m, 1 H ϩ 1 H, CH A ϩ B], 1.73Ϫ
2.07 (m, 2 H ϩ 2 H, CH2 A ϩ B), 2.25 (br. s, 1
H ϩ 1 H, NH A ϩ B), 3.71Ϫ3.82 (m, 1 H,
*CH A), 3.82Ϫ3.92 (m, 1 H, *CH B), 5.56 (d,
J ϭ 1.3 Hz, 1 H, NCHN A), 5.59 (d, J ϭ
1.3 Hz, 1 H, NCHN B), 5.68 (s, 1 H, PhNH
A), 5.72 (s, 1 H, PhNH B), 6.55Ϫ6.73 (m, 2 H
ϩ 2 H, Harom.. A ϩ B), 6.80Ϫ6.94 (m, 1 H ϩ 1
H, Harom. A ϩ B), 6.10Ϫ7.43 (m, 7 H ϩ 7 H,
Harom. A ϩ B)[b]
173.7[b]
4cc
3295, 2970, 1715, 1605,
1500, 1460, 1390, 1370,
1290, 1265, 1225, 1175,
1090, 1070, 755, 700, 670
21.8, 21.9, 23.8, 23.9, 25.4, 309 [Mϩ] (99), 196 (14),
25.5, 42.5, 55.6, 56.4, 75.1, 175 (12), 174 (36), 134
75.4, 114.1, 114.4, 121.8,
121.9, 127.3, 128.0, 129.4,
129.6, 129.7, 129.8, 130.1,
138.2, 139.1, 145.6, 145.8,
174.9, 175.2[b]
(10), 132 (100), 108 (23),
106 (83), 105 (30), 92 (26),
91 (23), 90 (28), 76 (26),
65 (15)
4cd
3230, 2970, 1710, 1605,
1525, 1500, 1410, 1350,
0.84Ϫ1.06 [m, 6 H ϩ 6 H, CH(CH3)2 A ϩ B],
1.36Ϫ1.66 [m, 1 H ϩ 1 H, CH A ϩ B], 1.66Ϫ
21.8, 22.0, 23.7, 23.8, 25.1, 354 [Mϩ] (42), 151 (100),
25.4, 42.2, 43.1, 54.8, 55.7, 134 (49), 108 (51), 105
1315, 1255, 1225, 1090, 860, 2.00 (m, 2 H ϩ 2 H, CH2 A ϩ B), 2.73 (br. s, 1
70.6, 71.0, 113.9, 114.0,
121.8, 122.1, 125.1, 125.8,
127.7, 129.1, 129.6, 129.7,
129.9, 130.0, 134.0, 134.2,
134.5, 134.9, 145.5, 145.6,
149.7, 150.2, 174.6,
(29), 93 (43), 92 (45), 86
(53), 77 (62), 65 (36), 57
(37), 55 (34), 43 (52), 41
(45)
830, 755, 700, 670, 645, 610
H ϩ 1 H, NH A ϩ B), 3.61Ϫ3.75 (m, 1 H,
*CH A), 3.84Ϫ3.98 (m, 1 H, *CH B), 6.32Ϫ
6.39 (m, 1 H ϩ 1 H ϩ 1 H, PhNH A ϩ B,
NCHN A), 6.42 (d, J ϭ 1.0 Hz, 1 H, NCHN
B), 6.54Ϫ6.65 (m, 2 H, Harom. B), 6.65Ϫ6.76
(m, 2 H, Harom. A), 6.78Ϫ6.95 (m, 1 H ϩ 1 H,
Harom. A ϩ B), 7.05Ϫ7.27 (m, 2 H ϩ 2 H, Harom.
A ϩ B), 7.38Ϫ8.00 (m, 4 H ϩ 4 H, Harom. A ϩ
B)[b]
175.2[b]
4ce
4dc
3260, 2960, 2930, 2870,
1700, 1600, 1495, 1390,
1370, 1255, 1235, 1155, 800, H, CHCH2, NH], 3.53 (dd, J1 ϭ 10.0, J2
0.88Ϫ1.06 [m, 6 H, CH(CH3)2], 1.34 (s, 3 H,
CCH3), 1.44 (s, 3 H, CCH3), 1.75Ϫ2.03 [m, 4
21.9, 23.7, 24.9, 25.4, 27.6, 261 [Mϩ] (91), 126 (49),
42.0, 55.2, 77.4, 114.1,
121.4, 129.4, 147.6,
176.7[b]
108 (39), 98 (19), 93 (31),
92 (26), 83 (72), 76 (17),
69 (17), 64 (20), 58 (100),
43 (20), 42 (35), 41 (29)
ϭ
750, 695, 665, 620
9.6 Hz, 1 H, *CH), 6.21 (s, 1 H, PhNH),
6.72Ϫ6.82 (m, 2 H, Harom.), 6.82Ϫ6.93 (m, 1 H,
[b]
Harom.), 7.12Ϫ7.25 (m, 2 H, Harom.
)
3300, 1710, 1600, 1495,
1455, 1430, 1390, 1360,
2.92Ϫ3.34 (m, 2 H ϩ 2 H, CH2 A ϩ B), 3.44
(br. s, 1 H ϩ 1 H, NH A ϩ B), 3.85Ϫ4.09 (m, 1
27.3, 27.5, 57.1, 57.7, 74.4, 382 [Mϩ] (46), 170 (44),
74.9, 109.8, 109.9, 111.1,
111.9, 112.1, 118.2, 118.3,
118.5, 118.6, 120.7, 120.8,
123.9, 124.0, 127.1, 127.4,
127.5, 127.6, 127.8, 128.2,
128.4, 128.5, 136.1, 136.2,
139.2, 139.9, 146.6, 146.7,
172.8, 173.3[c]
161 (18), 146 (18), 143
(16), 131 (17), 130 (100),
117 (18), 93 (41), 92 (18),
77 (18)
1340, 1305, 1230, 1090, 745, H ϩ 1 H, *CH A ϩ B) 5.39 (d, J ϭ 0.8 Hz, 1
700, 665
H, NCHN A), 5.42 (d, J ϭ 0.5 Hz, 1 H,
NCHN B),6.32Ϫ6.44 (m, 2 H, Harom. A), 6.44Ϫ
6.56 (m, 2 H, Harom. B), 6.56Ϫ6.72 (m, 1 H ϩ 1
H, Harom. A ϩ B), 6.90Ϫ7.49 (m, 11 H ϩ 11 H,
Harom. A ϩ B), 7.52Ϫ7.69 (m, 1 H ϩ 1 H, Harom.
A ϩ B), 7.71 (s, 1 H, PhNH B), 7.76 (s, 1 H,
PhNH A), 10.9 (br. s, 1 H ϩ 1 H, NHarom. A ϩ
B)[c]
3844
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3840Ϫ3849

Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl Compounds
Table 2. (Continued)
FULL PAPER
IR (KBr), ν˜ (cmϪ1
)
1H NMR[a], δ (ppm), J (Hz)
13C NMR, δ (ppm)
MS (70 eV), m/z (%)
4de
3310, 1705, 1605, 1500,
1460, 1395, 1375, 1345,
1260, 1180, 1160, 750, 700,
670, 640, 630
1.13 (s, 3H CH3), 1.23 (s, 3H CH3), 3.01 and
3.18 (AB of ABX, JAB ϭ 14.9, JAX ϭ 7.3, JBX
ϭ 4.1 Hz, 2 H, CH2), 3.30 (br. s, 1 H, NH),
3.76 (dd, J1 ϭ 7.3, J2 ϭ 4.1 Hz, 1 H, *CH),
6.47Ϫ6.62 (m, 2 H, Harom.), 6.62Ϫ6.75 (m, 1 H,
Harom.), 6.90Ϫ7.15 (m, 5 H, Harom.), 7.18Ϫ7.24
(m, 1 H, Harom.), 7.34Ϫ7.44 (m, 1 H, Harom.),
25.2, 26.6, 26.7, 56.6, 75.8,
109.8, 111.2, 112.1, 118.3,
118.5, 120.8, 124.0, 127.4,
128.4, 136.1, 148.0,
173.3[c]
334 [Mϩ] (68), 205 (13),
170 (73), 143 (29), 131
(19), 130 (100), 117 (17),
98 (46), 93 (44), 92 (27),
77 (17), 58 (14), 42 (16)
7.52Ϫ7.64 (m, 1 H, Harom.), 7.91 (s, 1 H,
[c]
PhNH), 10.9 (s, 1 H, NHarom.
)
285 [Mϩ] (100), 178 (21),
150 (65), 123 (25), 121
(46), 108 (24), 98 (38), 93
(39), 92 (46), 82 (80),
4ee
3400Ϫ2300, 1700, 1630,
1600, 1500, 1430, 1395,
1370, 1330, 1310, 1260,
1235, 1980, 1110, 1080, 940,
900, 820, 750, 700, 630
1.20 (s, 1 H, CH3), 1.23 (s, 1 H, CH3), 2.88
(app d, J ϭ 5.1 Hz, 2 H, CH2), 3.68 (app t, J ϭ
5.1 Hz, 1 H, *CH), 6.35Ϫ6.53 (m, 2 H, Harom.),
6.61Ϫ6.74 (m, 1 H, Harom.), 6.83 (d, J ϭ
1.2 Hz, 1 H, Himidazole), 7.00Ϫ7.15 (m, 2 H,
Harom.), 7.28 (br. s, 1 H, NH), 7.65 (d, J ϭ
25.3, 25.9, 27.9, 56.0, 75.9,
112.1, 116.6, 118.4, 128.4,
133.8, 134.6, 148.1,
172.9[c]
81 (44), 65 (23), 58 (42)
1.2 Hz, 1 H, Himidazole), 7.89 (s, 1 H, PhNH),
[c]
8.21 (s, 1 H, NHimidazole
)
[a]
[b]
[c]
A: Diastereoisomer A; B: diastereoisomer B. Solvent: CDCl3. Solvent: [D6]DMSO.
Figure 1. ORTEP view of the two diastereoisomers (A and B) of 5-isobutyl-2-(2-nitrophenyl)-3-(phenylamino)imidazolidin-4-one (4cd)
4
(Table 3) show that H4 and H5 exhibit a long-range J cor- 3dc, which promptly cyclizes to give a mixture of the two
5
relation to Η3, and H5 exhibits a long-range J correlation diastereoisomers 4dc(A) and 4dc(B). At this point, only
to H1. These results are consistent with the structure pro- 4dc(A) has the correct geometry to react with a second mol-
posed in Figure 2 where H3, H4 and H5 are all in a syn re- ecule of 2c, leading to 5dc, while 4dc(B), with its disfav-
lationship.
oured structure, isomerises to 4dc(A) via the imine 3dc.
To explain the stereochemical course of the reaction, we
We suggested a similar mechanism for the formation of
suggest the following mechanism, using 5dc as the example 5ec. Cyclisation reactions like this one involving the imidaz-
(Scheme 3). Compound 1d reacts with 2c to form the imine ole ring have been reported for histamine and histidine un-
Eur. J. Org. Chem. 2003, 3840Ϫ3849
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3845

G. Verardo, P. Geatti, P. Matinuzzi, M. Merli, N. Toniutti
FULL PAPER
Scheme 2
Conclusions
The results described herein widen the synthetic avail-
ability of a variety of heterocyclic compounds with rigid
frameworks containing natural amino acid moieties. Fur-
thermore, the presence of two amino nitrogen atoms of dif-
ferent reactivity could be attractive for the design of new
peptidomimetic structures having biological activity.
Figure 2. Structure of 1,10-diphenyl-2-(phenylamino)-2,9,10a-triaz-
acyclopenta[b]fluoren-3-one (5dc)
Experimental Section
General: All reagents were commercial quality (Aldrich, Fluka) and
were used without further purification. The α-amino acid phenylhy-
drazides 1aϪc were prepared as described previously.[1] The reac-
tions were monitored by TLC performed on silica gel plates (Kie-
selgel 60 F254, Merck). Preparative thick-layer chromatography was
performed on silica gel (Kieselgel 60 F254, 2 mm thickness, Merck).
The imidazolidin-4-one derivatives 4 obtained could not be purified
by absorption chromatography since they decompose extensively
upon prolonged contact on silica gel or alumina. Direct-inlet mass
spectra (DI-MS) were obtained with a Fisons TRIO 2000 gas chro-
matograph/mass spectrometer, working in the positive-ion, 70-eV,
electron-impact mode. Spectra were recorded in the range 35Ϫ450
u. Temperatures between 150 and 250 °C were suitable for volatilis-
ing all the compounds into the ion source. IR spectra were obtained
with a Nicolet FT-IR Magna 550 spectrophotometer using the KBr
Table 3. 1H NMR spectroscopic data of 5dc and corresponding
H,H-COSY correlations in the aliphatic region (Figure 2)
δ (ppm), [J (Hz)]
H,H-COSY
H1
H2
H3
H4
H5
3.00 (ddd) [14.8; 11.0; 1.6 Hz]
3.35 (dd) [14.8; 4.2 Hz]
4.06 (dddd) [11.0; 4.2; 2.4; 0.5 Hz]
5.00 (d) [2.4 Hz]
H2, H3, H5
H1, H3
H1, H2, H4, H5
H3
5.14 (d) [0.5 Hz]
H1
der acidic conditions.[8] Additionally, many derivatives con-
taining the β-carboline moiety present in 5dc have been de-
scribed extensively in the literature. This subunit, found in
many naturally occurring compounds, is the subject of
extensive chemical and biochemical research[9] because of
its pharmacological importance. Furthermore, the β-carbo-
line system containing a reduced form of its pyridine ring
has received special attention because this framework is pre-
sent in several alkaloids.[10]
technique for solids and recorded in the range 4000Ϫ400 cmϪ1
.
1H and 13C NMR spectra were recorded with a Bruker AC-F 200
spectrometer at 200 and 50 MHz, respectively, using CDCl3 at
room temperature or [D6]DMSO at 40 °C as solvents. The posi-
tions of the peaks are reported as δ values relative to TMS. Some
1H multiplets are characterised by the term app (apparent): this
refers only to their appearance and may be an oversimplification.
Optical rotations were determined at 20 °C (concentration in g/
3846
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3840Ϫ3849

Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl Compounds
FULL PAPER
Scheme 3
100 mL of solvent) using a POLAX-D polarimeter purchased from
ATAGO (Japan). Elemental analyses were performed with a Carlo
Erba Mod. 1106 elemental analyser. Melting points were deter-
mined with an automatic Mettler (Mod. FP61) melting point ap-
paratus and are not corrected.
a dessicator because of its hygroscopicity. Spectroscopically pure
product 1e was obtained (2.49 g, 82%). M.p. (dec.) 122 °C. [α]D
ϩ19.1 (c ϭ 1.0, MeOH). IR (KBr): ν˜ ϭ 3654Ϫ2549 broad, 1674,
1605, 1494, 1247, 756, 696, 625 cmϪ1. MS (70 eV): m/z (%) ϭ 245
[Mϩ] (21), 164 (5), 138 (6), 123 (5), 121 (7), 110 (100), 108 (20), 93
(36), 92 (21), 83 (25), 82 (74), 81 (26), 77 (13). 1H NMR
([D6]DMSO): δ ϭ 2.67 and 2.90 (AB of ABX, 2 H, JAB ϭ 14.4,
ϭ
Tryptophan Phenylhydrazide (1d): -Tryptophan methyl ester hy-
drochloride (3.00 g, 11.80 mmol) and freshly distilled phenylhydra-
zine (6.00 mL, 61.03 mmol) were mixed and stirred under Ar at 60
°C for 16 h. The resulting solid reaction mixture was cooled to
room temperature, triturated in Et2O (70 mL) and then stirred vig-
orously for 1 h. The solid was filtered off, vigorously stirred with
Na2CO3·10H2O (6.70 g) and H2O (25 mL) for 2 h and then filtered
and washed with H2O (10 mL). Spectroscopically pure product 1d
was obtained (3.13 g, 90%). M.p. 182 °C. [α]D ϭ ϩ53.0 (c ϭ 1.0,
MeOH). IR (KBr): ν˜ ϭ 3328, 3286, 1667, 1603, 1543, 1499, 1476,
JAX ϭ 7.8, JBX ϭ 5.8 Hz, *CHCH2), 3.58 (dd, J1 ϭ 7.6, J2
5.9 Hz, 1 H, *CH), 3.71 (br. s, 2 H, NH2), 6.58Ϫ6.77 (m, 4 H,
arom. ϩ NH), 6.81 (d, J ϭ 1.0 Hz, 1 H, Himidazole), 7.02Ϫ7.17 (m,
ϭ
H
2 H, Harom.), 7.54 (d, J ϭ 1.0 Hz, 1 H, Himidazole), 7.56 (s, 1 H,
NH), 8.21 (s, 1 H, NHimidazole) ppm. 13C NMR ([D6]DMSO): δ ϭ
32.8, 54.0, 112.2, 116.2, 118.3, 128.4, 133.0, 134.5, 149.2,
174.2 ppm. C12H15N5O (245.28): calcd. C 58.76, H 6.16, N 28.55;
found C 58.78, H 6.15, N 28.52.
1430, 1231, 1099, 934, 862, 770, 743, 695, 490 cmϪ1. MS (70 eV): Reactions of the Phenylhydrazides of Alanine (1a), Phenylalanine
m/z (%) ϭ 294 [Mϩ] (13), 277 (3), 170 (10), 164 (12), 163 (6), 159 (1b) and Leucine (1c) with Propanal (2a), Benzaldehyde (2c) and 2-
(11), 143 (5), 130 (100), 117 (7), 115 (5), 108 (7), 93 (37), 92 (15),
Nitrobenzaldehyde (2d): A solution of the appropriate -amino acid
77 (12). H NMR ([D6]DMSO): δ ϭ 2.84 and 3.12 (AB of ABX, phenylhydrazide (1aϪc, 2.80 mmol) and aldehyde (2a,c,d,
2 H, JAB ϭ 14.0, JAX ϭ 7.4, JBX ϭ 6.7 Hz, *CHCH2), 3.17 (br. s, 3.08 mmol) in absolute EtOH (30 mL) was stirred under Ar at 70
1
2 H, NH2), 3.63 (app t, 1 H, J ϭ 6.3 Hz, *CH), 6.50Ϫ7.45 (m, °C (50 °C when 2a was used) for 2 h (monitored by TLC: silica;
12 H, Harom. ϩ 2 NH), 10.92 (s, 1 H, NHindole) ppm. 13C NMR EtOAc). The EtOH was distilled off under reduced pressure and
([D6]DMSO): δ ϭ 31.5, 54.5, 110.6, 111.3, 112.2, 118.2, 118.3,
excess aldehyde was removed by dissolving the residue in CH2Cl2
118.6, 120.9, 123.8, 127.4, 128.5, 136.3, 149.2, 174.5 ppm. (10 mL) and stirring with saturated aqueous Na2S2O5 (0.5 mL) for
C17H18N4O (294.36): calcd. C 69.37, H 6.16, N 19.03; found C
69.33, H 6.18, N 19.00.
1 h. The organic phase was separated and dried with anhydrous
Na2SO4 and then the solvent was evaporated to afford a residue
consisting of the two diastereoisomers of either 5-methyl-2-phenyl-
3-(phenylamino)imidazolidin-4-one (4ac), 5-benzyl-2-ethyl-3-(phe-
nylamino)imidazolidin-4-one (4ba), 5-benzyl-2-phenyl-3-(phenyl-
amino)imidazolidin-4-one (4bc), 5-benzyl-2-(2-nitrophenyl)-3-(phe-
nylamino)imidazolidin-4-one (4bd), 5-isobutyl-2-phenyl-3-(phenyl-
amino)imidazolidin-4-one (4cc) or 5-isobutyl-2-(2-nitrophenyl)-3-
(phenylamino)imidazolidin-4-one (4cd).
Histidine Phenylhydrazide (1e): -Histidine methyl ester dihydro-
chloride (3.00 g, 12.40 mmol) and freshly distilled phenylhydrazine
(6.10 mL, 61.90 mmol) were mixed and stirred under Ar at 60 °C
for 16 h. The resulting solid reaction mixture was cooled to room
temperature, triturated in Et2O (70 mL) and then stirred vigorously
for 1 h. The solid was filtered off, added to a mixture of
Na2CO3·10H2O (7.00 g), H2O (2.00 mL) and CH2Cl2 (70 mL) and
then stirred vigorously for 1 h. The solid was filtered off, washed
with CH2Cl2 (2 ϫ 20 mL) and dissolved in boiling iPrOH. The
Reaction of Tryptophan Phenylhydrazide (1d) and Benzaldehyde
(2c): A solution of 1d (0.44 g, 1.50 mmol) and 2c (0.16 mL,
insoluble material was filtered off and, after partial evaporation of 1.58 mmol) in EtOH (15 mL) was stirred under Ar at 50 °C for
the solvent under reduced pressure, the remaining solution was ad-
ded dropwise to Et2O (50 mL) whilst stirring to form a solid white
precipitate, which was filtered under Ar, dried and then stored in
3 h (monitored by TLC: silica; EtOAc/TEA, 99:1). The EtOH was
distilled off under reduced pressure and excess 2c was removed by
dissolving the residue in CH2Cl2 (10 mL) and stirring with satu-
Eur. J. Org. Chem. 2003, 3840Ϫ3849
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3847

G. Verardo, P. Geatti, P. Matinuzzi, M. Merli, N. Toniutti
FULL PAPER
rated aqueous Na2S2O5 (0.3 mL) for 1 h. The organic phase was
1H NMR ([D6]acetone): δ ϭ 3.00 (ddd, J1 ϭ 14.8, J2 ϭ 11.0, J3 ϭ
separated and dried with anhydrous Na2SO4 and then the solvent 1.6 Hz, 1 H, *CHCHH), 3.35 (dd, J1 ϭ 14.8, J2 ϭ 4.2 Hz, 1 H, *
was evaporated to afford a residue consisting of the two dia-
stereoisomers of 5-(1H-indol-3-ylmethyl)-2-phenyl-3-(phenylami-
no)imidazolidin-4-one (4dc).
CHCHH), 4.06 (dddd, J1 ϭ 11.0, J2 ϭ 4.2, J3 ϭ 2.4, J4 ϭ 0.5 Hz,
1 H, *CH), 5.00 (d, J ϭ 2.4 Hz, 1 H, NCHNCO), 5.14 (d, J ϭ
0.5 Hz, 1 H, NCHCindole), 6.45Ϫ6.55 (m, 2 H, Harom.), 6.61Ϫ6.68
(m, 1 H, Harom.), 6.74 (s, 1 H, PhNH), 6.93Ϫ7.15 (m, 6 H, Harom.),
7.30Ϫ7.46 (m, 7 H, Harom.), 7.53Ϫ7.68 (m, 3 H, Harom.), 9.72 (s, 1
Reaction of Alanine Phenylhydrazide (1a) with 2,2-Dimethylpropanal
(2b): A solution of 1a (0.50 g, 2.80 mmol), 2b (0.91 mL, 8.40 mmol)
and PTSA (0.05 g, 0.28 mmol) in toluene (30 mL) was stirred under
Ar at 60 °C for 6 h (monitored by TLC: silica; EtOAc). After evap-
oration of the solvent under reduced pressure, the residue was dis-
solved in CH2Cl2 (10 mL) and stirred vigorously with
Na2CO3·10H2O (0.48 g) and H2O (0.13 mL) for 30 min. The mix-
ture was dried with anhydrous Na2SO4 and filtered and then the
CH2Cl2 was evaporated. Removal of excess 2b under vacuum (45
°C, 50 Pa) and trituration of the residue in pentane yielded one of
the two diastereoisomers of 2-tert-butyl-5-methyl-3-(phenylamino)-
imidazolidin-4-one (4ab).
1
H, NHindole) ppm. H NMR ([D6]DMSO): δ ϭ 2.94 (br. dd, J1 ϭ
14.4, J2 ϭ 11.0 Hz, 1 H, *CHCHH), 3.32 (dd, J1 ϭ 14.8, J2
ϭ
4.3 Hz, 1 H, *CHCHH), 4.01 (app dq, J1 ϭ 10.9, J2 ϭ 3.9, J3 ϭ
2.4 Hz, 1 H, *CH), 4.90 (d, J ϭ 2.4 Hz, 1 H, NCHNCO), 5.00 (s,
1 H, NCHCindole), 6.34Ϫ6.46 (m, 2 H, Harom.), 6.53Ϫ6.66 (m, 1 H,
Harom.), 6.88Ϫ7.13 (m, 6 H, Harom.), 7.19Ϫ7.30 (m, 1 H, Harom.),
7.32Ϫ7.63 (m, 10 H, Harom.), 7.67 (s, 1 H, PhNH), 10.62 (s, 1 H,
NHindole) ppm. 13C NMR ([D6]DMSO): δ ϭ 23.7, 52.6, 55.8, 76.0,
107.3, 111.1, 111.8, 117.9, 118.5, 118.7, 121.1, 126.2, 128.1, 128.4,
129.2, 129.3, 129.5, 133.3, 135.3, 136.1, 136.3, 146.8, 170.2 ppm.
C31H26N4O (470.57): calcd. C 79.12, H 5.57, N 11.91; found C
79.10, H 5.55, N 11.92.
Reactions of the Phenylhydrazides of Alanine (1a), Phenylalanine
(1b), Leucine (1c), Tryptophan (1d) and Histidine (1e) with Acetone
(2e): A solution of the appropriate -amino acid phenylhydrazide
(1aϪe, 2.80 mmol) and 2e (1.03 mL, 14.00 mmol) in EtOH (30 mL)
was stirred under Ar at 50 °C for 5 h (monitored by TLC: silica;
EtOAc). Evaporation of EtOH and excess 2e under reduced press-
ure afforded a residue consisting of either 2,2,5-trimethyl-3-(phe-
nylamino)imidazolidin-4-one (4ae), 5-benzyl-2,2-dimethyl-3-(phe-
nylamino)imidazolidin-4-one (4bc), 5-isobutyl-2,2-dimethyl-3-(phe-
nylamino)imidazolidin-4-one (4ce), 5-(1H-indol-3-ylmethyl)-2,2-di-
methyl-3-(phenylamino)imidazolidin-4-one (4dc) or 5-(1H-
imidazol-4-ylmethyl)-2,2-dimethyl-3-(phenylamino)imidazolidin-4-
one (4ee) in a spectroscopically pure form.
4,5-Diphenyl-6-(phenylamino)-3,4,5,6,7a,8-hexahydro-1,3,4a,6-te-
traaza-s-indacen-7-one (5ec): A solution of histidine phenylhydra-
zide (1e, 0.34 g, 1.40 mmol) and benzaldehyde (2c, 0.57 mL,
5.60 mmol) in EtOH (15 mL) was stirred at 50 °C under Ar for
15 h (monitored by TLC: silica; MTBE/EtOH, 70:30). After evap-
oration of the solvent under reduced pressure, the residue was tritu-
rated in hexane and filtered. Spectroscopically pure product 5ec
was obtained (0.47 g, 79%). M.p. 142 °C. [α]D ϭ ϩ16.5 (c ϭ 1.5,
MeOH). IR (KBr): ν˜ ϭ 3500Ϫ2760 broad, 1730, 1610, 1500, 1455,
1320, 1290, 1225, 1100, 940, 755, 705, 665 cmϪ1. MS (70 eV): m/z
(%) ϭ 421 [Mϩ] (24), 196 (40), 165 (23), 194 (26), 170 (19), 169
(24), 105 (36), 104 (30), 103 (24), 93 (100), 92 (33), 91 (26), 77 (42).
1H NMR ([D6]DMSO): δ ϭ 2.42 (dd, J1 ϭ 16.0, J2 ϭ 9.1 Hz, 1
H, *CHCHH), 3.18 (dd, J1 ϭ 15.9, J2 ϭ 1.1 Hz, 1 H, *CHCHH),
4.34 (app dt, J1 ϭ 9.1, J2 ϭ 1.6 Hz, 1 H, *CH), 5.07 (d, J ϭ 2.2 Hz,
1 H, NCHNCO), 6.02Ϫ6.20 (m, 2 H, Harom. ϩ NCHCimidazole),
6.49 (s, 1 H, PhNH), 6.60Ϫ7.70 (m, 14 H, Harom.), 7.90 (s, 1 H,
Reactions of the Phenylhydrazides of Alanine (1a) and Phenylalanine
(1b) with 2-Pentanone (2f), Acetophenone (2g) and 4-Nitroaceto-
phenone (2h): A solution of the appropriate -amino acid phenylhy-
drazide (1aϪb, 2.80 mmol), ketone (2fϪh, 5.60 mmol) and PTSA
(0.05 g, 0.28 mmol) in toluene (30 mL) was stirred under Ar at 85
°C for 24 h (monitored by TLC: silica; EtOAc). After evaporation
of the solvent under reduced pressure, the residue was dissolved in
CH2Cl2 (10 mL) and then stirred vigorously with Na2CO3·10H2O
(0.48 g) and H2O (0.13 mL) for 30 min. The mixture was dried with
anhydrous Na2SO4 and filtered and then the CH2Cl2 was evapo-
rated. The excess ketone was removed by preparative TLC on silica
gel (eluent: EtOAc) to give a mixture of the two distereoisomers
of either 2,5-dimethyl-2-phenyl-3-(phenylamino)imidazolidin-4-one
(4ag), 5-benzyl-2-methyl-3-(phenylamino)-2-propylimidazolidin-4-
one (4bf) or 5-benzyl-2-methyl-2-(4-nitrophenyl)-3-(phenylamino)-
imidazolidin-4-one (4bh).
H
imidazole), 8.13 (s, 1 H, NHimidazole) ppm. 13C NMR ([D6]DMSO):
δ ϭ 21.9, 53.9, 70.9, 78.1, 111.8, 119.1, 122.8, 125.0, 125.9, 128.1,
128.2, 128.4, 128.6, 128.7, 129.2, 137.7, 138.3, 145.8, 146.6,
170.0 ppm. C26H23N5O (421.50): calcd. C 74.09, H 5.50, N 16.62;
found C 74.10, H 5.53, N 16.65.
X-ray Crystallography: X-ray diffraction analysis of the sample was
carried out using a Bruker-Axs three-circle diffractometer with a
Smart-Apex CCD detector using graphite-monochromated Mo-Kα
˚
radiation (λ ϭ 0.7107 A) at 298 K. 10601 reflections were obtained
up to 2θ ϭ 59.4° from a monoclinic crystal [molecular formula
C38H44N8O6, space group P21, a ϭ 9.769(5), b ϭ 22.121(9), c ϭ
Ϫ3
˚
1,10-Diphenyl-2-(phenylamino)-1,2,3a,4,9,10a-triazacyclopenta[b]- 9.798(5) A, β ϭ 115.49(3), V ϭ 1911.14, Z ϭ 2, D ϭ 1.23 g·cm
,
fluoren-3-one (5dc): A solution of tryptophan phenylhydrazide (1d,
0.44 g, 1.50 mmol) and benzaldehyde (2c, 0.76 mL, 4.50 mmol) in
EtOH (15 mL) was stirred under Ar at 50 °C for 40 h (monitored
by TLC: silica; MTBE/EtOH, 70:30). The EtOH was distilled off
under reduced pressure and excess 2c was removed by dissolving
the residue in CH2Cl2 (10 mL) and then stirring with saturated
aqueous Na2S2O5 (2.5 mL) for 1 h. The organic phase was sepa-
rated and dried with anhydrous Na2SO4 and then the solvent was
evaporated. Spectroscopically pure product 5dc was obtained
linear absorption coefficient 0.085 mmϪ1] of dimension 0.48 ϫ 0.25
ϫ 0.07 mm. Unit-cell dimensions were calculated from least-
squares refinement of the d values obtained from 3136 reflections
in the θ range 2Ϫ12°. Because of the low quality of the crystal
from the diffraction viewpoint, the reflections with θ Ͼ 21° were
considered unobserved, thus the number of unique reflections [Ͼ
2σ(I)] used to solve and refine the crystal structure was limited to
4043 (R on the equivalent reflections 0.0288). The structure was
solved using the programme SHELXS-86[11] and refined with
(0.68 g, 96%). M.p. 194 °C. [α]D ϭ Ϫ76.0 (c ϭ 0.6, MeOH). IR SHELXL-97[12] using the full-matrix least-squares method. The
(KBr): ν˜ ϭ 3340, 1635, 1605, 1500, 1460, 1410, 1330, 1310, 1270,
non-hydrogen atoms were refined anisotropically; the H atoms were
placed in calculated positions. The final value of R on the observed
1230, 1060, 1050, 840, 750, 705, 650, 630 cmϪ1. MS (70 eV): m/z
(%) ϭ 470 [Mϩ] (28), 335 (20), 245 (6), 244 (17), 243 (14), 232 (39), reflections was 0.0648 and the value of R on all the data set was
220 (21), 219 (59), 218 (100), 217 (33), 146 (33), 93 (31), 77 (15).
0.0844 (Rw ϭ 0.1539, goodness of fit ϭ 1.071, parameters/Fo ra-
3848
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3840Ϫ3849

Condensation Reaction Between α-Amino Acid Phenylhydrazides and Carbonyl Compounds
FULL PAPER
[3]
[3a] F. Kusuda, Y. Matsuo, E. Seto, U. S. Patent 3,284,447, 1966;
tio ϭ 8.63). The absolute structure was fixed by comparison with
a known structure. CCDC-208797 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
[3b]
Chem. Abstr. 1967, 66, 28772q.
F. Kusuda, M. Murayama,
Y. Matsuo, H. Okumura, N. Tatewaki, Japan Patent 3095,
1967; Chem. Abstr. 1967, 66, 115707r.
T. Poloski, Tetrahedron 1985, 41, 611Ϫ616.
U. Zelavi, D. Ben-Ishai, J. Org. Chem. 1961, 26, 1097Ϫ1101.
R. E. Harmon, V. L. Rizzo, S. K. Gupta, J. Heterocycl. Chem.
1970, 7, 439Ϫ442.
[4]
[5]
[6]
[7] [7a]
A. F. Hegarty, in The Chemistry of the Hydrazo, Azo and
Azoxy Groups (Ed.: S. Patai), John Wiley & Sons, London,
1975, pp. 647Ϫ651. [7b]G. Verardo, N. Toniutti, A. G. Giuman-
ini, Can. J. Chem. 1998, 76, 1180Ϫ1187.
A. R. Katritzky, C. W. Rees, in Comprehensive Heterocyclic
Chemistry (Ed.: K. T. Potts), Pergamon Press, New York, 1984,
vol. 5, part 4A, pp. 404Ϫ405.
M. Balon, J. Hidalgo, P. Guardado, M. A. Munoz, C. Car-
mona, J. Chem. Soc., Perkin Trans. 2 1993, 91Ϫ97 and refer-
ences cited therein.
R. J. Sundberg, The Chemistry of Indoles, Academic Press, New
York, 1970, pp. 231Ϫ269.
G. M. Sheldrick, in Crystallographic Computing 3 (Ed.: G. M.
Sheldrick, C. Kruger, R. Goddard), Oxford University Press,
New York, 1985, pp. 175Ϫ189.
G. M. Sheldrick, SHELXL-97, Universität Göttingen, 1997.
Received April 23, 2003
Acknowledgments
[8]
[9]
Financial support was obtained from MIUR (PRIN 2000Ϫ2001).
P. G. is the recipient of a three-year scholarship from the Ministry
of Agriculture. The authors are grateful to Mr P. Padovani for ex-
pert instrumental maintenance.
[1]
[10]
[11]
G. Verardo, N. Toniutti, A. Gorassini, A. G. Giumanini, Eur.
J. Org. Chem. 1999, 2943Ϫ2948.
[2] [2a]
F. Hoffmann-La Roche & Co., A.-G. Neth, Appl. Patent
[2b]
6,409,088, 1965; Chem. Abstr. 1965, 63, 2978g.
M. Lasperas, J. Taillades, A. Commeyras, A. Perez-Rubalcaba,
Bull. Soc. Chim. Fr. 1984, 329Ϫ337.
Reson. 1984, 22, 176Ϫ179.
R. Pascal,
[2c]
[12]
T. Poloski, Org. Magn.
Eur. J. Org. Chem. 2003, 3840Ϫ3849
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3849